1-(Benzothiazol-2-yl)-4-(1-phenylmethyl) piperazines: dopamine receptor subtype specific ligands

ABSTRACT

Disclosed are compounds of the formula:                    
     or pharmaceutically acceptable addition salts thereof wherein: 
     R 1  and R 2  are the same or different and represent hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, hydroxy, amino, mono- or di(C 1 -C 6 )alkylamino, cyano or trifluoromethyl; 
     Ar represents aryl or heteroaryl, each of which is optionally substituted with R 3 , R 4  and/or R 4 ; 
     R 3 , R 4 , and R 6  independently represent hydrogen, halogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, perfluoro(C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkoxy, or SO 2 NH 2 ; or 
     R 3  and R 4  together with the atoms to which they are attached represent a ring having 5-7 atoms; and 
     R 5  represents hydrogen or C 1 -C 6  alkyl, 
     which compounds are useful for the treatment and/or prevention of neuropsychological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.

This application claims benefit of priority from U.S. Provisional Appl.Ser. No. 60/091,210 filed Jun. 30, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to1-(benzothiazol-2-yl)-4-(1-phenylmethyl)piperazines and pharmaceuticalcompositions containing such compounds. It also relates to the use ofsuch compounds in the treatment or prevention of psychotic disorderssuch as schizophrenia and other central nervous system diseases.

2. Description of the Related Art

The therapeutic effect of conventional antipsychotics, known asneuroleptics, is generally believed to be exerted through blockade ofdopamine receptors. However, neuroleptics are frequently responsible forundesirable extrapyramidal side effects (EPS) and tardive dyskinesias,which are attributed to blockade of D₂ receptors in the striatal regionof the brain. The dopamine D₄ receptor subtype has recently beenidentified (Nature, 350: 610 (Van Tol et al., 1991); Nature, 347: 146(Sokoloff et al., 1990)). Its unique localization in limbic brain areasand its differential recognition of various antipsychotics indicatesthat the D₄ receptor plays a major role in the etiology ofschizophrenia. Selective D₄ antagonists are considered effectiveantipsychotics free from the neurological side effects displayed byconventional neuroleptics.

J. Heterocycl. Chem., 32: 707-718 (Orjales et al., 1995) disclosespiperazinebenzothiazole derivatives said to be useful asantihistaminics.

J. Med. Chem., 37: 1320-1325 (Monge et al., 1994) disclosespiperazinebenzothiazole derivatives as 5-HT₃ antagonists and 5-HT₄agonists.

Published International Application WO 9420494 disclosespiperazinebenzothiazole derivatives said to be capable of stimulatinggastrointestinal motility.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withdopamine receptor subtypes. Accordingly, a broad aspect of the inventionis directed to a compound of Formula I:

or pharmaceutically acceptable addition salts thereof wherein:

R₁ and R₂ are the same or different and represent hydrogen, halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, hydroxy, amino, mono- ordi(C₁-C₆)alkylamino, cyano or trifluoromethyl;

Ar represents aryl or heteroaryl, each of which is optionallysubstituted with R₃, R₄ and/or R₆;

R₇, R₈, R₉, and R₁₀ are the same or different and represent hydrogen orC₁-C₆ alkyl;

R₃, R₄, and R₆ independently represent hydrogen, halogen, hydroxy, C₁-C₆alkyl, C₁-C₆ alkoxy, perfluoro(C₁-C₆)alkyl, perfluoro(C₁-C₆)alkoxy, orSO₂NH₂, provided that when Ar is phenyl and two or three of R₃, R₄, andR₆ are methoxy, no two methoxy groups may be positioned ortho to eachother on the phenyl ring; or

R₃ and R₄ together with the atoms to which they are attached represent aring having 5-7 atoms;

R₅ represents hydrogen or C₁-C₆ alkyl.

Dopamine D₄ receptors are concentrated in the limbic system (Science,265: 1034 (Taubes, 1994)) which controls cognition and emotion.Therefore, compounds that interact with these receptors are useful inthe treatment of cognitive disorders. Such disorders include cognitivedeficits which are a significant component of the negative symptoms(social withdrawal and unresponsiveness) of schizophrenia. Otherdisorders include those involving memory impairment or attention deficitdisorders.

Compounds of the present invention demonstrate high affinity andselectivity in binding to the D₄ receptor subtype. These compounds aretherefore useful in treatment of a variety of neuropsychologicaldisorders, such as, for example, schizophrenia, psychotic depression andmania. Other dopamine-mediated diseases such as Parkinsonism and tardivedyskinesias can also be treated directly or indirectly by modulation ofD₄ receptors.

Compounds of this invention are also useful in the treatment ofdepression, memory-impairment or Alzheimer's disease by modulation of D₄receptors since they exist selectively in areas known to control emotionand cognitive functions.

Thus, in another aspect, the invention provides methods for treatmentand/or prevention of neuropsychochological or affective disordersincluding, for example, schizophrenia, mania, dementia, depression,anxiety, compulsive behavior, substance abuse, memory impairment,cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonismand dystonia, and motion disorders related to the use of neurolepticagents. In addition, the compounds of the invention are useful intreatment of depression, memory-impairment or Alzheimer's disease.Further, the compounds of the present invention are useful for thetreatment of other disorders that respond to dopaminergic blockade,e.g., substance abuse and obsessive compulsive disorder. These compoundsare also useful in treating the extrapyramidal side effects associatedwith the use of conventional neuroleptic agents.

In yet another aspect, the invention provides pharmaceuticalcompositions comprising compounds of Formula I.

In another aspect, the invention provides intermediates useful in thepreparation of compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, this invention provides compounds of Formula I whichinteract with dopamine subtypes.

Preferred compounds of Formula I are those where R₁ and R₂ are hydrogen.More preferred compounds of Formula I are those wherein R₁ and R₂ arehydrogen and Ar is not unsubstituted phenyl, i.e., phenyl substitutedwith at least one non-hydrogen substituent. Particularly preferredcompounds of Formula I are those where Ar is phenyl or naphthyl, each ofwhich is optionally substituted with up to three of the groups listedabove. In these particularly preferred compounds, when Ar is phenyl andR₁ and R₂ are hydrogen, R₃, R₄, and R₆ may not all be hydrogensimultaneously. Other preferred compounds of Formula I are those whereR₇, R₈, R₉, and R₁₀ are hydrogen or C₁-C₂ alkyl.

In preferred compounds, when Ar is phenyl and two or three of R₃, R₄,and R₆ are methoxy or ethoxy, no two methoxy groups may be methoxygroups positioned ortho to each other; more preferably no methoxy groupmay be positioned ortho to another methoxy group or to an ethoxy group.Even more preferably, when Ar is phenyl and two or three of R₃, R₄, andR₆ are methoxy or ethoxy, no methoxy or ethoxy group may be in an orthoposition on the phenyl ring with respect to another methoxy or ethoxygroup. Highly preferred compounds of the invention include those whereone and only one of R₃, R₄, and R₆ is C₁-C₆ alkoxy when Ar is phenyl.

More preferred compounds of Formula I are those where Ar is

Preferred compounds of the invention include those of Formula II:

wherein

R₁ and R₂ are the same or different and represent hydrogen, halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, hydroxy, amino, mono- ordi(C₁-C₆)alkylamino, cyano or trifluoromethyl;

R₃ and R₄ are the same or different and represent hydrogen, halogen,hydroxy, C₁-C₆ alkyl, trifluoromethyl, trifluoromethoxy, or SO₂NH₂,provided that not both R₃ and R₄ are hydrogen simultaneously; and

R₅ represents hydrogen or C₁-C₆ alkyl.

Preferred compounds of Formula II include those where R₅ is hydrogen.Other preferred compounds of Formula II include those where R₅ ishydrogen, and R₃ is halogen or C₁-C₆ alkyl. More preferred compounds ofFormula II are where R₄ is halogen, R₅ is hydrogen, and R₃ is halogen orC₁-C₆ alkyl. Particularly preferred compounds of Formula II are thosewhere R₁ and R₂ are hydrogen, R₄ is halogen, R₅ is hydrogen, and R₃ ishalogen or C₁-C₆ alkyl. A highly preferred group of compounds are thosewhere R₄ is halogen in the meta position of the phenyl ring, R₅ ishydrogen, and R₃ is halogen or C₁-C₆ alkyl.

Highly preferred compounds of Formula II are those where the phenylcarrying R₃ and R₄ is selected from:

Other preferred compounds of the invention are those of Formula III:

wherein:

R₁ and R₂ are the same or different and represent hydrogen, halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, hydroxy, amino, mono- ordi(C₁-C₆)alkylamino, cyano or trifluoromethyl;

R₆ represents hydrogen, halogen, hydroxy, C₁-C₆ alkyl, trifluoromethyl,trifluoromethoxy, or SO₂NH₂; and

R₅ represents hydrogen or C₁-C₆ alkyl.

Preferred compounds of Formula III include those where R₅ is hydrogen.Other preferred compounds of Formula III include those where R₅ ishydrogen, and R₆ is hydrogen, halogen or C₁-C₆ alkyl. More preferredcompounds of Formula III are where R₆ is hydrogen. Particularlypreferred compounds of Formula III are those where R₁, R₂, and R₅ arehydrogen.

The invention also provides intermediates useful in preparing compoundsof Formula I. These intermediates have Formulae IV and V.

where R₁ and R₂ are defined as above for Formula I; and Z is a leavinggroup, such as halogen.

Preferred compounds of Formula IV are where R₁ and R₂ are hydrogen,methyl or ethyl; and Z is chloro.

where R₁, R₂, and R₇-R₁₀ are defined as above for Formula I.

Preferred compounds of Formula V are where R₁ and R₂ are hydrogen.Particularly preferred compounds of Formula V are those where R₁, R₂,and R₇-R₁₀ are hydrogen, methyl, or ethyl.

In certain situations, the compounds of Formula I may contain one ormore asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table Iand their pharmaceutically acceptable acid addition salts. In addition,if the compound of the invention is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)_(n)—COOH where nis 0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

Where a compound exists in various tautomeric forms, the invention isnot limited to any one of the specific tautomers. The invention includesall tautomeric forms of a compound.

By “C₁-C₆ alkyl” or “lower alkyl” in the present invention is meantstraight or branched chain alkyl groups having 1-6 carbon atoms, suchas, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,3-hexyl, and 3-methylpentyl. Preferred C₁-C₆ alkyl groups are methyl,ethyl, propyl, butyl, cyclopropyl and cyclopropylmethyl.

By “C₁-C₆ alkoxy” or “lower alkoxy” in the present invention is meantstraight or branched chain alkoxy groups having 1-6 carbon atoms, suchas, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy,hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

By the term “halogen” in the present invention is meant fluorine,bromine, chlorine, and iodine.

By aryl or “Ar” is meant an aromatic carbocyclic group having a singlering (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which isoptionally mono-, di-, or trisubstituted with, e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy. Preferred Ar groups are phenyl and2-naphthyl.

By aryl or “Ar” is also meant heteroaryl groups where heteroaryl isdefined as 5, 6, or 7 membered aromatic ring systems having at least onehetero atom selected from the group consisting of nitrogen, oxygen andsulfur. Examples of heteroaryl groups are pyridyl, pyrimidinyl,pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, furanyl,quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which can optionallybe substituted with, e.g., halogen, lower alkyl, lower alkoxy, loweralkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, andhydroxy.

As noted above, R₃ and R₄ may be connected together to form another ringwith the atoms to which they are attached on the parent aryl orheteroaryl group. Thus, R₃ and R₄ may represent an alkylene, alkenylene,alkyleneoxy, alkylenedioxy, alkyleneazo, or alkylenediazo chain thattogether with the atoms to which they are attached form a ring having5-7 atoms. For example, Ar may be an optionally substituted naphthylgroup or a bicyclic oxygen-containing group of the formula

wherein the heterocyclic oxygen containing ring has a total of from 5 to7 ring members, the heterocyclic ring being saturated or unsaturated,and optionally substituted.

Preferred examples of bicyclic oxygen-containing groups are:

As an additional example, Ar may be a bicyclic nitrogen-containing groupof the formula

wherein E is methylene or nitrogen and the heterocyclic oxygencontaining ring has a total of from 5 to 7 ring members, theheterocyclic ring being saturated or unsaturated, and optionallysubstituted.

Preferred examples of bicyclic nitrogen-containing groups are:

Representative 1-(benzothiazol-2-yl)-4-(1-phenylmethyl)piperazines ofthe present invention are shown in Table 1. The number below eachcompound is its compound number.

The invention also pertains to the use of compounds of general Formula Iin the treatment of neuropsychological disorders. The selectiveinteraction of compounds of the invention with dopamine receptorsresults in the pharmacological activity of these compounds.

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

A representative synthesis of the1-(benzothiazol-2-yl)-4-(1-phenylmethyl)-piperazines of the invention ispresented in Scheme I.

wherein Ar, R₁, R₂, R₇, R₈, R₉, and R₁₀ are as defined above for Formula1.

As shown in Scheme I, a 2-chlorobenzothiazole IV may be condensed withan appropriately substituted piperazine to provide a1-(benzothiaol-2-yl)piperazine V. Piperazine V may then be reductivelyalkylated with an arylaldehyde VI using, for example, sodiumcyanoborohydride to provide a1-(benzothiaol-2-yl)-4-(1-phenylmethyl)piperazine of Formula I.

Alternatively, compounds of Formula I may be prepared according to theScheme II.

wherein Ar, R₁, R₂, R₇, R₈, R₉, and R₁₀ are as defined above for Formula1, and X represents a leaving group, e.g., a halide.

As illustrated in Scheme II, a 1-(benzothiaol-2-yl)piperazine V may bealkylated using an appropriate arylmethyl compound VII where X is ahalide, sulphonate ester or the like to provide a1-(benzothiaol-2-yl)-4-(1-phenylmethyl)piperazine of Formula 1.

In either of these approaches to the compounds of Formula I, thosehaving skill in the art will recognize that the starting materials maybe varied and additional steps employed to produce compounds encompassedby the present invention.

The disclosures of all articles and references mentioned in thisapplication, including patents, are incorporated herein by reference.

The preparation of the compounds of the present invention is illustratedfurther by the following examples which are not to be construed aslimiting the invention in scope or spirit to the specific procedures andcompounds described in them.

The starting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available organiccompounds, or prepared using well known synthetic methods.

EXAMPLE 1

1. 1-(Benzothiazol-2-yl)piperazine

A solution of 2-chlorobenzothiazole (5 g) in 20 mL of toluene is addeddropwise to a refluxing solution of piperazine (20 g) in 150 mL oftoluene. The solution is heated for an additional 24 hours, and aftercooling at 0° C. for about 30 minutes, filtered. The filtrate isextracted with 10% acetic acid and the aqueous extracts are washed withether, basified and extracted with dichloromethane. The dichloromethanelayer is washed with water, dried and concentrated. The concentratedmaterial is placed under vacuum overnight (6.8 g, m.p. 63-64° C.). ¹HNMR (CDCl₃) 7.62 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.29 (td,J=7.6, 1.2 Hz, 1H), 7.07 (t, J=8.0 Hz, 1H), 3.61 (t, J=5.2 Hz, 4H), 3.00(t, J=5.2 Hz, 4H).

2. 1-(Benzothiazol-2-yl)-4-(1-[3-chlorophenyl]methyl)piperazinehydrochloride

A solution of 1-(benzothiazol-2-yl)piperazine (220 mg, 1.0 mmol) and3-chlorobenzaldehyde (150 mg) in methanol (10 mL) is made and the pHadjusted to about 4 using acetic acid. Sodium cyanoborohydride (500 mg)is then added and the reaction mixture stirred at room temperatureovernight during which time a white precipitate forms. The precipitate,1-(Benzothiazol-2-yl)-4-(1-[3-chlorophenyl]-methyl)piperazine (Compound5), is collected by vacuum filtration and washed with methanol. Thehydrochloride salt, Compound 5A, is obtained from an isopropanolsolution (320 mg, 88%, m.p. 238-241° C.). ¹H NMR (DMSO) 7.82 (d, J=7.3Hz, 1H), 7.76 (s, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.51 (m, 4H), 7.31 (td,J=7.3, 1.2 Hz, 1H), 7.12 (t, J=7.3 Hz, 1H), 4.38 (s br, 2H), 4.15 (d br,J=12.8 Hz, 2H), 3.66 (t br, J=12.2 Hz, 2H). 3.39 (d br, J=11.6 Hz, 2H),3.20 (s br, 2H).

EXAMPLE 2

1-(Benzothiazol-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazinehydrochloride

A solution of 1-(benzothiazol-2-yl)piperazine (220 mg, 1.0 mmol) and4-chlorobenzyl chloride (180 mg) in acetonitrile (10 mL) containingpotassium carbonate (500 mg) is strirred and heated at 60° C. for 4 h.After cooling, the reaction is partitioned between ether and water andthe organic layer is extracted with 1 N HCl. The combined acid extractsare basified and extracted with chloroform. The organic layer is driedand concentrated to provide the product as a white solid (Compound 1,300 mg, 87%). The oxalate salt, Compound 1A, is obtained from anisopropanol solution (m.p. 216-218° C.). ¹H NMR (DMSO) 7.75 (d, J=7.3Hz, 1H), 7.40 (m, 5H), 7.29 (t, J=7.6 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H),3.65 (s br, 2H), 3.36 (s br, 4H), 2.60 (s br, 4H).

EXAMPLE 3

The following compounds are prepared essentially according to themethods set forth above in Examples 1 and 2:

(a) 1-(benzothiazol-2-yl)-4-(1-[4-methylphenyl]methyl)piperazine oxalate(Compound 2A, m.p. 243-244° C.)

(b) 1-(benzothiazol-2-yl)-4-(1-[3,4-difluorophenyl]methyl)piperazineoxalate (Compound 3A, m.p. 223-224° C.)

(c) 1-(benzothiazol-2-yl)-4-(1-[2-naphthyl]methyl)piperazine oxalate(Compound 4A, m.p. 158-160° C.)

EXAMPLE 4

Assay for D₂ and D₄ Receptor Binding Activity

The utility of compounds of this invention is indicated by the assaysfor dopamine receptor subtype affinity described below.

Pellets of COS cells containing recombinantly produced D₂ or D₄receptors from African Green monkey were used for the assays. The sampleis homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 4° C.and pH 7.4. The sample is then centrifuged at 30,000×g and resuspendedand rehomogenized. The sample is then centrifuged as described and thefinal tissue sample is frozen until use. The tissue is resuspended 1:20(wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl.

Incubations are carried out at 48° C. and contain 0.4 ml of tissuesample, 0.5 nM ³H-YM 09151-2 (Nemonapride,cis-5-Chloro-2-methoxy-4-(methylamino)-N-(2-methyl-2-(phenylmethyl)-3-pyrroli-dinyl)benzamide)and the compound of interest in a total incubation of 1.0 ml.Nonspecific binding is defined as that binding found in the presence of1 mM spiperone; without further additions, nonspecific binding is lessthan 20% of total binding. Binding characteristics for representativecompounds of the invention for the D₂ and D₄ receptor subtypes are shownin Table 2.

TABLE 2 Compound Number¹ D₄ K_(i) (nM) D₂ K_(i) (nM) 1A 14 >4000  2A 253508 4A 76 3508

The above data are representative of the K_(i) values for compounds ofthe invention; all compounds of the invention are active in the aboveassay. Further, compounds of the invention generally possess a Ki valuefor the dopamine D₄ receptor subtype of below about 100 nM.

The binding constants of compounds of Formula I for the D₄ receptor,expressed in nM, generally range from about 5 nanomolar (nM) to about100 nanomolar (nM). These compounds typically have binding constants forthe D₂ receptor of from about 500 nM to at least 4000 nM. Thus, thecompounds of the invention are generally at least about 5 time moreselective for the D₄ receptor than the D₂ receptor. Preferably, thesecompounds are at least 10, and more preferably at least 20-50, timesmore selective for the D₄ receptor than the D₂ receptor. Mostpreferably, these compounds are at least 100 times more selective forthe D₄ receptor than the D₂ receptor.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula:

or pharmaceutically acceptable addition salts thereof wherein: R₁ and R₂are the same or different and represent hydrogen, halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkylthio, hydroxy, amino, mono- ordi(C₁-C₆)alkylamino, cyano or trifluoromethyl; R₆ represents hydrogen,halogen, hydroxy, C₁-C₆ alkyl, trifluoromethyl, trifluoromethoxy, orSO₂NH₂; and R₅ represents hydrogen or C₁-C₆ alkyl.
 2. A compoundaccording to claim 1, wherein R₅ is hydrogen.
 3. A compound according toclaim 2, wherein R₆ is halogen or C₁-C₆ alkyl.
 4. A compound accordingto claim 2, wherein R₆ is halogen.
 5. A compound according to 4, whereinR₁ and R₂ are hydrogen.
 6. A compound which is selected from:1-(benzothiazol-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine oxalate;1-(benzothiazol-2-yl)-4-(1-[4-methylphenyl]methyl)piperazine oxalate;1-(benzothiazol-2-yl)-4-(1-[3,4-difluorophenyl]methyl)piperazineoxalate; 1-(benzothiazol-2-yl)-4-(1-[2-naphthyl]methyl)piperazineoxalate; 1-(benzothiazol-2-yl)-4-(1-[3-chlorophenyl]methyl)piperazinehydrochloride; and1-(benzothiazol-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine oxalate. 7.A compound which is selected from1-(benzothiazol-2-yl)-4-(1-[3,4-diflurophenyl]methyl)piperazine and1-(benzothiazol-2-yl)-4-(1-[2-naphthyl]methyl)piperazine.
 8. Apharmaceutical composition comprising a therapeutically effective amountof a compound or salt according to claim 1 and a pharmaceuticallyacceptable carrier.